Survey of Ophthalmology
Volume 44, Issue 3 , Pages 235-246 , November 1999

Tumor Suppressor Genes in Ophthalmology

  • J.William Harbour, MD

      Affiliations

    • Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
    • Corresponding Author InformationReprint address: J. William Harbour, MD, Center for Ocular Oncology, Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, Box 8096 660 South Euclid Avenue, St. Louis, MO 63110.

References 

  1. —— . Identification and characterization of the tuberous sclerosis gene on chromosome 16. The European Chromosome 16 Tuberous Sclerosis Consortium. Cell. 7. 1993;5:1305–1315
  2. Bartek J, Bartkova J, Lukas J. The retinoblastoma protein pathway in cell cycle control and cancer. Exp Cell Res. 1997;237:1–6
  3. Basu TN, Gutmann DH, Fletcher JA, et al.  Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients [see comments]. Nature. 1992;356:713–715
  4. Bischoff JR, Kirn DH, Williams A, et al.  An adenovirus mutant that replicates selectively in p53-deficient human tumor cells [see comments]. Science. 1996;274:373–376
  5. Bodmer WF, Bailey CJ, Bodmer J, et al.  Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. 1987;328:614–616
  6. Carbonara C, Longa L, Grosso E, et al.  9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene. Hum Mol Genet. 1994;3:1829–1832
  7. Cawthon RM, Weiss R, Xu GF, et al.  A major segment of the neurofibromatosis type 1 gene (cDNA sequence, genomic structure, and point mutations [published erratum appears in Cell 1990 Aug 10;62(3):following 608]). Cell. 1990;62:193–201
  8. Chen YN, Sharma SK, Ramsey TM, et al.  Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists [see comments]. Proc Natl Acad Sci USA. 1999;96:4325–4329
  9. Chintala SK, Fueyo J, Gomez-Manzano C, et al.  Adenovirus-mediated p16/CDKN2 gene transfer suppresses glioma invasion in vitro. Oncogene. 1997;15:2049–2057
  10. Crossey PA, Foster K, Richards FM, et al.  Molecular genetic investigations of the mechanism of tumorigenesis in von Hippel-Lindau disease (analysis of allele loss in VHL tumours). Hum Genet. 1994;93:53–58
  11. Crossey PA, Richards FM, Foster K, et al.  Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet. 1994;3:1303–1308
  12. Davies DR, Armstrong JG, Thakker N, et al.  Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. Am J Hum Genet. 1995;57:1151–1158
  13. Day ML, Foster RG, Day KC, et al.  Cell anchorage regulates apoptosis through the retinoblastoma tumor suppressor/E2F pathway. J Biol Chem. 1997;272:8125–8128
  14. Denhardt DT. Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell (the potential for multiplex signalling). Biochem J. 1996;318:729–747
  15. Donehower LA, Harvey M, Slagle BL, et al.  Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature. 1992;356:215–221
  16. el-Deiry WS, Tokino T, Velculescu VE, et al.  WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75:817–825
  17. Fearon ER. Human cancer syndromes (clues to the origin and nature of cancer). Science. 1997;278:1043–1050
  18. Feldkamp MM, Gutmann DH, Guha A. Neurofibromatosis type 1 (piecing the puzzle together). Can J Neurol Sci. 1998;25:181–191
  19. Fodde R, Edelmann W, Yang K, et al.  A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc Natl Acad Sci USA. 1994;91:8969–8973
  20. Friend SH, Bernards R, Rogelj S, et al.  A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986;323:643–646
  21. Fung YK, Murphree AL, T'Ang A, et al.  Structural evidence for the authenticity of the human retinoblastoma gene. Science. 1987;236:1657–1661
  22. Giaccia AJ, Kastan MB. The complexity of p53 modulation (emerging patterns from divergent signals). Genes Dev. 1998;12:2973–2983
  23. Gibbs JB, Oliff A. The potential of farnesyltransferase inhibitors as cancer chemotherapeutics. Annu Rev Pharmacol Toxicol. 1997;37:143–166
  24. Gnarra JR, Tory K, Weng Y, et al.  Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994;7:85–90
  25. Gnarra JR, Ward JM, Porter FD, et al.  Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc Natl Acad Sci USA. 1997;94:9102–9107
  26. Green DR. Apoptotic pathways (the roads to ruin). Cell. 1998;94:695–698
  27. Gunduz K, Eagle RC, Shields CL, et al.  Invasive giant cell astrocytoma of the retina in a patient with tuberous sclerosis. Ophthalmology. 1999;106:639–642
  28. Gutmann DH. Recent insights into neurofibromatosis type 1 (clear genetic progress). Arch Neurol. 1998;55:778–780
  29. Gutmann DH, Wood DL, Collins FS. Identification of the neurofibromatosis type 1 gene product. Proc Natl Acad Sci USA. 1991;88:9658–9662
  30. Harbour JW. Overview of RB gene mutations in patients with retinoblastoma. Implications for clinical genetic screening. Ophthalmology. 1998;105:1442–1447
  31. Harbour JW, Lai SL, Whang-Peng J, et al.  Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science. 1988;241:353–357
  32. Harbour JW, Luo RX, Dei Santi A, et al.  CDK phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell. 1999;98:859–869
  33. Harbour JW, Murray TG, Hamasaki D, et al.  Local carboplatin therapy in transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci. 1996;37:1892–1898
  34. Harris CC, Hollstein M. Clinical implications of the p53 tumor-suppressor gene [see comments]. N Engl J Med. 1993;329:1318–1327
  35. Herwig S, Strauss M. The retinoblastoma protein (a master regulator of cell cycle, differentiation and apoptosis). Eur J Biochem. 1997;246:581–601
  36. Iliopoulos O, Kibel A, Gray S, Kaelin WG. Tumor suppression by the human von Hippel-Lindau gene product. Nat Med. 1995;1:822–826
  37. Iliopoulos O, Ohh M, Kaelin WG. pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from international translation initiation. Proc Natl Acad Sci USA. 1998;95:11661–11666
  38. Isshiki K, Seng BA, Elder DE, et al.  Chromosome 9 deletion in sporadic and familial melanomas in vivo. Oncogene. 1994;9:1649–1653
  39. Ito N, Rubin GM. Gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle. Cell. 1999;96:529–539
  40. Jacks T, Shih TS, Schmitt EM, et al.  Tumour predisposition in mice heterozygous for a targeted mutation in NF1. Nat Genet. 1994;7:353–361
  41. Jacks T, Weinberg RA. The expanding role of cell cycle regulators [comment]. Science. 1998;280:1035–1036
  42. Janssen K, Kuntze J, Busse H, Schmid KW. p53 oncoprotein overexpression in choroidal melanoma. Mod Pathol. 1996;9:267–272
  43. Jay M, McCartney AC. Familial malignant melanoma of the uvea and p53 (a Victorian detective story). Surv Ophthalmol. 1993;37:457–462
  44. Jones AC, Daniells CE, Snell RG, et al.  Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum Mol Genet. 1997;6:2155–2161
  45. Kaelin WG, Iliopoulos O, Lonergan KM, Ohh M. Functions of the von Hippel-Lindau tumour suppressor protein. J Intern Med. 1998;243:535–539
  46. Kaelin WG, Maher ER. The VHL tumour-suppressor gene paradigm. Trends Genet. 1998;14:423–426
  47. Kayes LM, Burke W, Riccardi VM, et al.  Deletions spanning the neurofibromatosis 1 gene (identification and phenotype of five patients). Am J Hum Genet. 1994;54:424–436
  48. Kibel A, Iliopoulos O, DeCaprio JA, Kaelin WG. Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C [see comments]. Science. 1995;269:1444–1446
  49. Kinzler KW, Nilbert MC, Su LK, et al.  Identification of FAP locus genes from chromosome 5q21. Science. 1991;253:661–665
  50. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87:159–170
  51. Knight WA 3d, Murphy WK, Gottlieb JA . Neurofibromatosis associated with malignant neurofibromas. Arch Dermatol. 1973;107:747–750
  52. Knudson AG. Mutation and cancer (statistical study of retinoblastoma). Proc Natl Acad Sci USA. 1971;68:820–823
  53. Kobayashi T, Mitani H, Takahashi R, et al.  Transgenic rescue from embryonic lethality and renal carcinogenesis in the Eker rat model by introduction of a wild-type Tsc2 gene. Proc Natl Acad Sci USA. 1997;94:3990–3993
  54. Korf BR. Ophthalmological issues in the neurofibromatoses. J Pediatr Ophthalmol Strabismus. 1996;33:255–259
  55. Latif F, Tory K, Gnarra J, et al.  Identification of the von Hippel-Lindau disease tumor suppressor gene [see comments]. Science. 1993;260:1317–1320
  56. Lee WH, Bookstein R, Hong F, et al.  Human retinoblastoma susceptibility gene (cloning, identification, and sequence). Science. 1987;235:1394–1399
  57. Legius E, Marchuk DA, Collins FS, Glover TW. Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet. 1993;3:122–126
  58. Li Y, Bollag G, Clark R, et al.  Somatic mutations in the neurofibromatosis 1 gene in human tumors. Cell. 1992;69:275–281
  59. Lin SC, Skapek SX, Lee EY. Genes in the RB pathway and their knockout in mice. Semin Cancer Biol. 1996;7:279–289
  60. Lohmann DR, Brandt B, Hopping W, et al.  The spectrum of RB1 germ-line mutations in hereditary retinoblastoma. Am J Hum Genet. 1996;58:940–949
  61. Lohmann DR, Brandt B, Hopping W, et al.  Distinct RB1 gene mutations with low penetrance in heredity retinoblastoma. Hum Genet. 1994;94:349–354
  62. Marcus DM, Rustgi AK, Defoe D, et al.  Retinal pigment epithelium abnormalities in mice with adenomatous polyposis coli gene disruption. Arch Ophthalmol. 1997;115:645–650
  63. McClatchey AI, Saotome I, Mercer K, et al.  Mice heterozygous for a mutation at the NF2 tumor suppressor locus develop a range of highly metastatic tumors. Genes Dev. 1998;12:1121–1133
  64. Merbs SL, Sidransky D. Analysis of p16 (CDKN2/MTS-12/INK4A) alterations in primary sporadic uveal melanoma. Invest Ophthalmol Vis Sci. 1999;40:779–783
  65. Merel P, Haong-Xuan K, Sanson M, et al.  Predominant occurrence of somatic mutations of the NF2 gene in meningiomas and schwannomas. Genes Chromosomes Cancer. 1995;13:211–216
  66. Miyoshi Y, Nagase H, Ando H, et al.  Somatic mutations of the APC gene in colorectal tumors (mutation cluster region in the APC gene). Hum Mol Genet. 1992;1:229–233
  67. Morgan DO. Principles of CDK regulation. Nature. 1995;374:131–134
  68. Morgenbesser SD, Williams BO, Jacks T, DePinho RA. p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens [see comments]. Nature. 1994;371:72–74
  69. Mulvihill JJ, Parry DM, Sherman JL, et al.  NIH conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). An update. Ann Intern Med. 1990;113:39–52
  70. Nakamura Y, Lathrop M, Leppert M, et al.  Localization of the genetic defect in familial adenomatous polyposis within a small region of chromosome 5. Am J Hum Genet. 1988;43:638–644
  71. Nickells RW, Zack DJ. Apoptosis in ocular disease (a molecular overview). Ophthalmic Genet. 1996;17:145–165
  72. Nielsen NH, Emdin SO, Cajander J, Landberg G. Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein. Oncogene. 1997;14:295–304
  73. Nyboer JH, Robertson DM, Gomez MR. Retinal lesion in tuberous sclerosis. Arch Ophthalmol. 1976;94:1277–1280
  74. Ohta M, Berd D, Shimizu M, et al.  Deletion mapping of chromosome region 9p21-p22 surrounding the CDKN2 locus in melanoma. Int J Cancer. 1996;65:762–767
  75. Olschwang S, Richard S, Boisson C, et al.  Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. Hum Mutat. 1998;12:424–430
  76. Olschwang S, Tiret A, Laurent-Puig P, et al.  Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients. Cell. 1993;75:959–968
  77. Onadim Z, Hogg A, Baird PN, Cowell JK. Oncogenic point mutations in exon 20 of the RB1 gene in families showing incomplete penetrance and mild expression of the retinoblastoma phenotype. Proc Natl Acad Sci USA. 1992;89:6177–6181
  78. Otterson GA, Chen WD, Coxon AB, et al.  Incomplete penetrance of familial retinoblastoma linked to germ-line mutations that result in partial loss of RB function. Proc Natl Acad Sci USA. 1997;94:12036–12040
  79. Park VM, Pivnick EK. Neurofibromatosis type 1 (NF1) (a protein truncation assay yielding identification of mutations in 73% of patients). J Med Genet. 1998;35:813–820
  80. Parr MJ, Manome Y, Tanaka T, et al.  Tumor-selective transgene expression in vivo mediated by an E2F-responsive adenoviral vector. Nat Med. 1997;3:1145–1149
  81. Plank TL, Yeung RS, Henske EP. Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Res. 1998;58:4766–4770
  82. Post GR, Brown JH. G protein-coupled receptors and signaling pathways regulating growth responses. FASEB J. 1996;10:741–749
  83. Povey S, Burley MW, Attwood J, et al.  Two loci for tuberous sclerosis (one on 9q34 and one on 16p13). Ann Hum Genet. 1994;58:107–127
  84. Prives C. Signaling to p53 (breaking the MDM2-p53 circuit). Cell. 1998;95:5–8
  85. Ragge NK, Baser ME, Klein J, et al.  Ocular abnormalities in neurofibromatosis. Am J Ophthalmol. 1995;120:634–641
  86. Rennebeck G, Kleymenova EV, Anderson R, et al.  Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development. Proc Natl Acad Sci USA. 1998;95:15629–15634
  87. Rouleau GA, Merel P, Lutchman M, et al.  Alteration in a new gene encoding a putative membrane-organizing protein causes neurofibromatosis type 2 [see comments]. Nature. 1993;363:515–521
  88. Rouleau GA, Seizinger BR, Wertelecki W, et al.  Flanking markers bracket the neurofibromatosis type 2 (NF2) gene on chromosome 22. Am J Hum Genet. 1990;46:323–328
  89. Ruttledge MH, Andermann AA, Phelan CM, et al.  Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease. Am J Hum Genet. 1996;59:331–342
  90. Ruttledge MH, Narod SA, Dumanski JP, et al.  Presymptomatic diagnosis for neurofibromatosis 2 with chromosome 22 markers. Neurology. 1993;43:1753–1760
  91. Sandig V, Brand K, Herwig S, et al.  Adenovirally transferred p16INK4/CDKN2 and p53 genes cooperate to induce apoptotic tumor cell death. Nat Med. 1997;3:313–319
  92. Selivanova G, Ryabchenko L, Jansson E, et al.  Reactivation of mutant p53 through interaction of a C-terminal peptide with the core domain. Mol Cell Biol. 1999;19:3395–3402
  93. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 [see comments]. Nature. 1993;366:704–707
  94. Sherr CJ. Cancer cell cycles. Science. 1996;274:1672–1677
  95. Shields JA, Shields CL, Shah PG, et al.  Lack of association among typical congenital hypertrophy of the retinal pigment epithelium, adenomatous polyposis, and Gardner syndrome. Ophthalmology. 1992;99:1709–1713
  96. Spirio L, Olschwang S, Groden J, et al.  Alleles of the APC gene (an attenuated form of familial polyposis). Cell. 1993;75:951–957
  97. Srivastava S, Zou ZQ, Pirollo K, et al.  Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome [see comments]. Nature. 1990;348:747–749
  98. Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999;398:422–426
  99. Tobal K, Warren W, Cooper CS, et al.  Increased expression and mutation of p53 in choroidal melanoma. Br J Cancer. 1992;66:900–904
  100. Traboulsi EI, Krush AJ, Gardner EJ, et al.  Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome. N Engl J Med. 1987;316:661–667
  101. Trofatter JA, MacCollin MM, Rutter JL, et al.  A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor [published erratum appears in Cell 1993 Nov 19;75(4):826]. Cell. 1993;72:791–800
  102. Trosko JE, Ruch RJ. Cell-cell communication in carcinogenesis. Frontiers in Bioscience. 1998;3:208–236
  103. van Bakel I, Sepp T, Ward S, et al.  Mutations in the TSC2 gene (analysis of the complete coding sequence using the protein truncation test (PTT)). Hum Mol Genet. 1997;6:1409–1414
  104. van der Luijt R, Khan PM, Vasen H, et al.  Rapid detection of translation-terminating mutations at the adenomatous polyposis coli (APC) gene by direct protein truncation test. Genomics. 1994;20:1–4
  105. van Slegtenhorst M, de Hoogt R, Hermans C, et al.  Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277:805–808
  106. van Slegtenhorst M, Nellist M, Nagelkerken B, et al.  Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet. 1998;7:1053–1057
  107. Wadayama B, Toguchida J, Shimizu T, et al.  Mutation spectrum of the retinoblastoma gene in osteosarcomas. Cancer Res. 1994;54:3042–3048
  108. Ward K, O'Connell P, Carey JC, et al.  Diagnosis of neurofibromatosis I by using tightly linked, flanking DNA markers. Am J Hum Genet. 1990;46:943–949
  109. Webster AR, Maher ER, Moore AT. Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation. Arch Ophthalmol. 1999;117:371–378
  110. Weintraub SJ, Prater CA, Dean DC. Retinoblastoma protein switches the E2F site from positive to negative element. Nature. 1992;358:259–261
  111. Wiggs J, Nordenskjold M, Yandell D, et al.  Prediction of the risk of hereditary retinoblastoma, using DNA polymorphisms within the retinoblastoma gene. N Engl J Med. 1988;318:151–157
  112. Windle JJ, Albert DM, O'Brien JM, et al.  Retinoblastoma in transgenic mice. Nature. 1990;343:665–669
  113. Xiao GH, Shoarinejad F, Jin F, et al.  The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J Biol Chem. 1997;272:6097–6100
  114. Zbar B, Kishida T, Chen F, et al.  Germline mutations in the von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat. 1996;8:348–357
  115. Zehavi C, Romano A, Goodman RM. Iris (Lisch) nodules in neurofibromatosis. Clin Genet. 1986;29:51–55
  116. Zwarthoff EC. Neurofibromatosis and associated tumour suppressor genes. Pathol Res Pract. 1996;192:647–657

 The author has no proprietary or commercial interest in any product or concept discussed in this article.

☆☆ The author was supported by a Research to Prevent Blindness, Inc. Career Development Award and by NEI grant K08 EY0038201.

PII: S0039-6257(99)00102-2

Survey of Ophthalmology
Volume 44, Issue 3 , Pages 235-246 , November 1999